生物
造血
福克斯O1
干细胞
祖细胞
细胞生物学
FOXO3公司
造血干细胞
髓样
免疫学
癌症研究
信号转导
蛋白激酶B
作者
Zuzana Tothova,Ramya Kollipara,Brian J. P. Huntly,Benjamin H. Lee,Diego H. Castrillon,Emmanuelle Passegué,Dana E. Cullen,Elizabeth McDowell,Suzan Lazo-Kallanian,Ifor R. Williams,Ronald A. DePinho,D. Gary Gilliland
出处
期刊:Blood
[American Society of Hematology]
日期:2006-11-16
被引量:1
标识
DOI:10.1182/blood.v108.11.439.439
摘要
Abstract Hematopoietic development and long-term homeostasis are tightly regulated by a dynamic balance of stem cell self-renewal and differentiation. To understand the role of the FoxO family of transcription factors in these processes, we studied the impact of somatic deletion of all FoxO genes in the adult hematopoietic system of mice engineered with the interferon-inducible Mx-Cre transgene and various conditional FoxO alleles: FoxO1L/L; FoxO3 L/L; and/or FoxO4 L/L. Cre-mediated excision of FoxO1, FoxO3 and FoxO4 (FoxO1/O3/O4L/L), resulted in myeloid lineage expansion, lymphoid developmental abnormalities and a marked decrease of the lineage-negative, Sca-1+, c-Kit+ (LSK) compartment, containing the hematopoietic stem cell (HSC) population, but normal numbers of myeloid progenitors. Furthermore, FoxO1/O3/O4L/L null bone marrow cells were defective in competitive and noncompetitive repopulation assays. This FoxO deficient defect correlated with enhanced cell cycling and increased apoptosis of HSC cells. Notably, there was an HSC-restricted elevation in the level of reactive oxygen species (ROS) that was not observed in committed progenitors, and was associated with decreased catalase and MnSOD expression. Furthermore, in vivo treatment with the anti-oxidative agent N-acetyl-cysteine (NAC) resulted in complete reversion of the FoxO deficient HSC phenotype. Taken together, these results demonstrate that, in the HSC compartment, FoxO proteins are mediators of quiescence and enhanced survival and play essential regulatory roles in the response to physiologic oxidative stress, a function that may contribute to the long-term regenerative potential of the hematopoietic stem cell compartment.
科研通智能强力驱动
Strongly Powered by AbleSci AI